Depression is a mental disease, which may lead to physical abnormalities and even to disabilities. In China, the morbidity rate of depression is approximately 3%˜5%. According to a prediction from the World Health Organization, depression may become a leading cause of disabilities and/or disease burden by the year 2030.
The symptoms of depression include mood fluctuations and the like, which directly interfere with people's daily life, including their work, study, sleep and diet. The symptoms of depression include loss of interest in daily activities, discomfort, sleep abnormality, susceptibility to fatigue, significant change in body weight, slow thinking, sense of guilt, sense of unworthiness, lack of concentration, and even increased propensity to commit suicide. In fact, not all the patients exhibit the same symptoms.
The etiologies of depression are low levels of monoamine neurotransmitters (e.g. norepinephrine (NE), serotonin (5-HT) and dopamine (DA)) in the central nervous system, and hypofunction of the corresponding receptors. At present, three types of medicaments are available for the treatment of depression. The first type is tricyclic antidepressants (TCAs). They increase the concentrations of NE and 5-HT in the brain, but have drawbacks including severe side effects like cardiotoxicity, additionally their effectiveness has a slow onset. The second type is monoamine oxidase inhibitors (MAOIs). MAOIs have an anti-depression effect that involves retarding the degradation of NE and 5-HT in the brain and thus extending the effective time of these transmitters. The third type is selective serotonin reuptake inhibitors (SSRIs). They increase the concentration of 5-HT in the synaptic cleft by inhibiting the reuptake of 5-HT in the presynaptic membrane, therefore the excitability of the 5-HT1A receptors in the postsynaptic membrane is improved, and concurrently the anti-depression effect is achieved. The advantage of SSRIs is that other neurotransmitter receptors are not affected, and consequently, SSRIs are relatively safe. However, some adverse effects are still observed as a result of non-selective effect on various subtypes of 5-HT receptors.
On Sep. 30, 2013, the U.S. Food and Drug Administration approved a new antidepressant drug named Vortioxetine, which was developed by Lundbeck and Takeda Pharmaceutical Co., Ltd. for treating depression. Its chemical name is 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine.
Vortioxetine is thought to have an anti-depression effect through its modulation of 5-HT receptors. It was suggested by nonclinical in vivo tests that Vortioxetine can increase the concentrations of neurotransmitters such as asserotonin, norepinephrine, dopamine, acetylcholine and histamine in certain regions of the brain. Nonclinical studies showed that Vortioxetine is able to modulate 5-HT3, 5-HT7, 5-HT1D, 5-HT1B, 5-HT1A, and 5-HT.
Vortioxetine is metabolized primarily through oxidation via cytochrome P450 isoenzymes CYP2D6, CYP3A4/5, CYP2C19, CYP2C9, CYP2A6, CYP2C8 and CYP2B6. Its metabolites are conjugated with glucuronic acid to produce new metabolites. Following a single oral dose of [14C]-labeled vortioxetine, approximately 59% and 26% of the radioactive metabolites were recovered in the urine and feces respectively.
When Vortioxetine is administered for treatment, the dosage is often increased in efforts to get desired curing effects, and dose escalation is often accompanied by the unfavorable metabolism of the drug. Since active metabolites produced by unfavorable metabolism are often key reasons for medicament toxicity and other side effects, many adverse reactions would be observed during the use of Vortioxetine for the treatment, including nausea, vomiting, diarrhea, headache, dizziness, etc. Given the foregoing, drugs that reduce the side effects and other toxicity of the antidepressants is an unmet medical need and has attracted broad scientific and medical attentions.